Comparative Pathology plays a crucial role in translational research by advancing our understanding of disease mechanisms across species, particularly in the context of cancer. This field leverages animal models, especially murine models, to study disease processes in a controlled setting that potentially mirrors human conditions. Rodent models, particularly genetically engineered mouse models, are commonly used in translational research to uncover molecular pathways, test therapeutic interventions, and validate biomarkers for human diseases. However, the ethical implications of animal research and the dedication to the 3R principles (Reduction, Refinement, Replacement) underscore the need for precise model selection and improved characterization. Comparative pathology can significantly enhance the understanding and comprehensive characterization of animal models, thereby enabling a more precise and selective application of these models in cancer research. By refining the understanding of these models’ applicability and limitations, comparative pathology aids in defining the role and necessity of specific animal models more accurately, ultimately promoting more targeted and responsible use. Particularly, including comparative pathologists in all stages of projects avoids misinterpretations, helps to guide researchers, and avoids unnecessary animal experiments. Beyond rodent models, naturally occurring cancers in companion animals, such as dogs and cats, present a unique and underutilized opportunity in biomedical research. These species spontaneously develop cancers with in a high percentage of cases morphological and biological characteristics similar to human tumors, providing an authentic model for studying tumorigenesis, metastatic behavior, and treatment responses in a clinically relevant environment. Notably, cancers in dogs and cats often show morphologic and genetic similarities (or discrepancies) to their human counterparts, allowing for more direct translational insights than genetically engineered rodent models can provide. This presentation will highlight the role of animal pathology in bridging the translational gap in cancer research, emphasizing the importance of using comparative pathology to improve translational outcomes while adhering to ethical standards. By integrating animal models with spontaneous diseases like they are occurring in companion animals, researchers can achieve a more comprehensive understanding of cancer biology and therapy, paving the way for advancements in both human and veterinary medicine.